The ventral pallidum (VP) may be a neurobiological substrate for the motivational aspects of opiate addiction, such as drug craving. Though grossly understudied, the neural adaptations that underlie the enhanced responding that occurs after repeated exposure to opiates likely parallel those mediating drug craving in the addict. Chronic opiates appear to induce long lasting changes in the ventral tegmental area (VTA) and the nucleus accumbens (NA). We hypothesize that VP neurons undergo a persistent adaptation to chronic opiate exposure. This may reflect an alteration in VTA and NA inputs, as well as changes in VP neurons themselves. To test these hypotheses, biochemical and electrophysiological comparisons will be made among these regions in rats that demonstrate morphine-induced sensitization. Specific Aim 1. To determine which aspects of the opioid receptor-mediated signal transduction system are involved in neuronal adaptations to chronic morphine treatments. Alterations in signal transduction may be critical mechanisms by which the brain adapts to chronic exposure to drugs of abuse. The effects of morphine-induced sensitization will be examined by this Aim by measuring G protein levels, adenylyl cyclase activity and immediate early gene induction. The results should indicate the biochemical underpinnings of functional changes seen in Aims 2 and 3. Specific Aim 2. To determine the ability of chronic morphine treatments to alter responses of VP and NA neurons to opioid agonists and antagonists. The opioid receptors that mediate morphine-induced sensitization and the physiological parallels to changes in opioid receptor-effector coupling seen during this sensitization are not known. Experiments in Aim 2 will use extracellular electrophysiology in combination with microiontophoretic application of opioid receptor subtype-specific drugs to provide the first examination of these issues for the VP and NA. Specific Aim 3. To determine if chronic morphine treatments alter opioid modulation of dopaminergic transmission from the VTA to the VP and NA. With extracellular electrophysiology, we recently revealed that opioids modulate dopamine transmission in the VP. As neuromodulation can occur on membrane events that are subthreshold to the generation of an action potential, intracellular recordings of VP and NA neurons in vivo will be used to determine if chronic morphine alters this modulation. Because the VP serves as a major output for the mesolimbic system, studies on this region are critical to understanding the consequences of neural adaptations of the brain's reward system. The proposed experiments should provide new insights for the development of more efficacious therapy for compulsive drug use and craving.